During development of protective immunity to microbes, dendritic cells play critical roles in bridging innate and adaptive immune responses. Like macrophages, dendritic cells respond directly to exposure to microbes by producing many cytokines and chemokines including IL-12 and type-I interferons that help coordinate local and systemic inflammatory responses. Dendritic cells are highly specialized to acquire antigens by phagocytosis and endocytosis, and exposure to microbial products induces maturation of the cells into potent stimulators of antigen-specific T-cells. This represents an important interface between the innate and adaptive immune systems in the host response to bacterial infection. In the absence of microbial stimulation, dendritic cells are thought to acquire host antigens and establish tolerance to self. This balance is essential for effective immunity. In this proposal, we aim to harness the resources of the GLUE consortium to define the endocytic receptors, ligands, and antigen processing machinery expressed by dendritic cells and their subsets in vivo, and to identify changes in dendritic cells undergoing maturation in vivo in response to chemically defined microbial and nonmicrobial stimuli. We will also identify MyD88 independent pathways of dendritic cell maturation in response to microbial products, and mimic these with specific pharmaceutical compounds. The program will generate several data sets including cDNA expression profiles and membrane/intracellular organelle protein profiles that will be of considerable use to the scientific community. Interactions with other bridging grants and with scientists driving the cutting edge technologies found in t e cores make this ambitious proposal possible.